Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4
 +
 CD25
 +
 Foxp3
 +
 regulatory T‐cell development in mice

Chen, Hui; Zhang, Lianjun; Zhang, Hongbing; Xiao, Yi; Shao, Lijuan; Li, Hongran; Yin, Hui; Wang, Ruoyu; Liu, Guangwei; Corley, Douglas A.; Yang, Zhongzhou; Zhao, Yong

doi:10.1096/fj.13-235408

Cited by 38 publications

(31 citation statements)

References 48 publications

(73 reference statements)

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“…However, in particular cases, manifested primarily for immune cells, rapamycin does not always reverse the TSC KO phenotype (32). This is due to plastic changes that occur early upon activation.…”

Section: Discussionmentioning

confidence: 97%

“…For instance, in the T cell lineage, TSC1 deletion in naive T cells confers cell quiescence (31). Differentiation of Foxp3-positive regulatory T cells is enhanced (32), and so is the differentiation of Th1 and Th17 cells (33). Interestingly, only some of these effects are reversed by rapamycin, suggesting that TSC deficiency irreversibly alters cell fate.…”

Section: Discussionmentioning

confidence: 99%

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mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion

Benhamron

Pattanayak

Berger³

et al. 2015

Molecular and Cellular Biology

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T he endoplasmic reticulum (ER) is the port of entry into the secretory pathway. ER stress is a state of imbalance between the protein-folding capacities and the amount of proteins in the ER. A network of signaling pathways termed the unfolded protein response (UPR) restores the disrupted balance in the ER or executes apoptosis when ER stress becomes terminal. In mammalian cells, the UPR operates in three parallel pathways named for ER stress sensors: inositol-requiring enzyme 1 (IRE1), protein kinaselike endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). These sensors activate downstream signals that regulate gene transcription and protein synthesis (1).Following a signal to differentiate into plasma cells (PCs), the ER of a B cell expands and becomes permissive for the synthesis, proper folding, assembly, and secretion of copious amounts of antibodies. For reasons that are not fully understood, the remodeling of the ER in the course of PC differentiation is controlled solely by the IRE1/X-box binding protein 1 (XBP-1) pathway of the UPR (2, 3). In the absence of XBP-1 or IRE1, B cells develop normally to the mature state but yield long-lived PCs that secrete small amounts of Igs (4-7).Mammalian target of rapamycin (mTOR) is a key metabolic serine/threonine kinase which exists in at least two multisubunit complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2 (8). mTORC1 funnels multiple signaling pathways from inside and outside the cell. When activated, mTORC1 promotes anabolic processes and enhances protein synthesis and cell growth (9). When it is inhibited, macroautophagy is induced (10). mTOR, primarily in the form of mTORC1, plays major roles in cancer and immune functions (11,12). Much of the knowledge on the role of mTOR in immune regulation has been obtained from loss-of-function experiments using rapamycin or analogs thereof. However, the effect that mTOR activation has on the immune system remains unclear. At the mature state of B cell development, mTOR is activated in response to Toll-like receptor and B cell receptor (BCR) stimulation downstream from the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Akt activates mTORC1 indirectly by reversing the tuber sclerosis complex (TSC) inhibition of mTOR. TSC is a complex that contains TSC1 and TSC2. Among many other functions, the mTOR pathway adjusts protein synthesis to the prosperity conditions of the cell. mTOR is activated when the ATP/AMP ratio or the intracellular pool of amino acids is high. The control of protein synthesis is regulated by mTOR-specific phosphorylation of 4E-BP1 and p70S6K1, both of which, when phosphorylated, mediate acceleration of protein synthesis and cell growth (13-15). Hence, inhibition of the mTOR globally reduces protein synthesis and cell size.We previously reported that mTOR is the predominant mechanism that controls protein synthesis in the late phase of lipopolysaccharide (LPS)-activated B cells, in a manner rigorously controlled by ER stress. Genetic ablation of TSC...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion

Benhamron

Pattanayak

Berger³

et al. 2015

Molecular and Cellular Biology

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“…mTOR, a serine-threonine kinase, plays a critical role in cell growth and proliferation, ribosome biogenesis, cytoskeletal organization, antibody switching and germinal centers [38,42,43,44]. mTOR complexes are activated by many factors, such as growth factors, hormones and cytokines for example [45].…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ Inhibits Nonopsonized Phagocytosis of Macrophages via an mTORC1-c/EBPβ Pathway

Wang¹,

Zhou²,

Sun³

et al. 2014

J Innate Immun

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Bacterial infection often follows virus infection due to pulmonary interferon-γ (IFN-γ) production during virus infection, which down-regulates macrophage phagocytosis. The molecular mechanisms for this process are still poorly understood. In the present study, IFN-γ treatment significantly inhibited the ability of mouse macrophages to phagocytize nonopsonized chicken red blood cells (cRBCs), bacteria and beads in vitro, while it enhanced IgG- and complement-opsonized phagocytosis. IFN-γ treatment decreased the expression of MARCO (macrophage receptor with collagenous structure) in macrophages. Macrophages showed lower binding to and phagocytic ability of cRBCs when MARCO was blocked with antibody. In addition, IFN-γ induced high activity of mTOR (mammalian target of rapamycin) and decreased the expression of c/EBPβ (CCAAT enhancer-binding protein β) in macrophages. Rapamycin, a specific mTOR inhibitor, significantly reversed the inhibitory effect of IFN-γ on nonopsonized phagocytosis of macrophages and restored c/EBPβ and MARCO expression. Biochemical assays showed that c/EBPβ directly bound to the MARCO gene promoter. Rapamycin significantly hampered the viral-bacterial synergy and protected influenza-infected mice from subsequent bacterial infection. Thus, IFN-γ inhibited the nonopsonized phagocytosis of macrophages through the mTOR-c/EBPβ-MARCO pathway. The present study offered evidence indicating that mTOR may be one of the key target molecules for the prevention of secondary bacterial infection caused by primary virus infection.

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“…mTORC1 is composed of the DEP domain-containing mTOR-interacting protein (DEPTOR), the mammalian lethal SEC13 protein 8 (MLST8), the proline-rich AKT substrate (PRAS40), and the regulatoryassociated protein of mTOR (Raptor). mTORC1 activity is directly induced by GTP-bound Rheb, which is inhibited by a heterotrimeric complex composed of TSC1 (hamartin), TSC2 (tuberin), and TBC1D7 (14,(16)(17)(18). As an essential component of mTORC1, Raptor has been well demonstrated to regulate both innate and adaptive immunity (19,20).…”

Section: N Atural Killer T Cells Have Been Well Defined As a Uniquementioning

confidence: 99%

Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function

Zhang

Tschumi

Corgnac

et al. 2014

The Journal of Immunology

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Invariant NKT (iNKT) cells play critical roles in bridging innate and adaptive immunity. The Raptor containing mTOR complex 1 (mTORC1) has been well documented to control peripheral CD4 or CD8 T cell effector or memory differentiation. However, the role of mTORC1 in iNKT cell development and function remains largely unknown. By using mice with T cell–restricted deletion of Raptor, we show that mTORC1 is selectively required for iNKT but not for conventional T cell development. Indeed, Raptor-deficient iNKT cells are mostly blocked at thymic stage 1–2, resulting in a dramatic decrease of terminal differentiation into stage 3 and severe reduction of peripheral iNKT cells. Moreover, residual iNKT cells in Raptor knockout mice are impaired in their rapid cytokine production upon αGalcer challenge. Bone marrow chimera studies demonstrate that mTORC1 controls iNKT differentiation in a cell-intrinsic manner. Collectively, our data provide the genetic evidence that iNKT cell development and effector functions are under the control of mTORC1 signaling.

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Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4 ⁺ CD25 ⁺ Foxp3 ⁺ regulatory T‐cell development in mice

Cited by 38 publications

References 48 publications

mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion

mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion

Interferon-γ Inhibits Nonopsonized Phagocytosis of Macrophages via an mTORC1-c/EBPβ Pathway

Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function

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Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4 + CD25 + Foxp3 + regulatory T‐cell development in mice

Cited by 38 publications

References 48 publications

mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion

mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion

Interferon-&#947; Inhibits Nonopsonized Phagocytosis of Macrophages via an mTORC1-c/EBPβ Pathway

Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function

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Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4 ⁺ CD25 ⁺ Foxp3 ⁺ regulatory T‐cell development in mice

Interferon-γ Inhibits Nonopsonized Phagocytosis of Macrophages via an mTORC1-c/EBPβ Pathway